The present invention relates generally to processes for producing .alpha.-pyridyl carbinol compounds. More particularly, it relates to a process for producing an .alpha.-2-pyridyl .alpha.-aryl carbinol or .alpha.-4-pyridyl .alpha.-aryl carbinol by reacting a 2- or 4-cyanopyridine with an aromatic carbonyl compound.
.alpha.-Pyridyl carbonol compounds, having the characteristic Py-C-OH grouping, where Py is a pyridyl group, have been widely studied and used in large quantities as intermediates in the production of antihistamines, for instance carbinoxamine, dioxylamine, Azacyclonol and the antihistamine terferadine (Seldane.RTM.). To date, several processes for producing these .alpha.-pyridyl carbinols have received substantial interest. For example, the "Emmert reaction" involves a reaction of pyridine and ketones in the presence of a magnesium or aluminum amalgam. The reaction product includes a mixture of 2- and 4-puridyl carbinols together with pinacols formed as byproducts. See, e.g. B. Emmert and E. Asendorf, Ber., 72, 1188 (1939); B. Emmert and E. Pirot, Ber., 74, 714 (1941); and C. H. Tilford, R. S. Shelton and M. G. Van Campen, Jr., J. Am. Chem. Soc., 70, 4001 (1948).
In the "Hammick reaction", .alpha.-pyridyl carbinols are produced by decarboxylation of picolinic acid in the an excess of aldehyde or ketone. See, e.g. P. Dyson and D. L. Hammick, J. Chem. Soc., 1724 (1937); and K. Mislow, J. Am. Chem. Soc., 69, 2559 (1947).
.alpha.-Pyridyl carbinols can also be prepared either by the action of pyridyl Grignard reagents on aldehydes or ketones, see, e.g., J. P. Wibuat and L. G. Heeringa, Recueil, 74, 1003 (1955), N. Furukawa, T. Shibutani, K. Matsumura, H. Fujihara, and S. Oae, Tetrahedro Lett., 27, 3899 (1966), or by the action of aryl Grignard reagents on pyridyl aldehydes, ketones or esters, see, e.g., A. E. Tshitschibabin and S. W. Benewolenskaja, Ber., 61, 547 (1928); Y. Kasuya and K. Fujie, Yakugaku Zasshi., 78, 551 (1958) [Chem. Abstr., 52, 17196i (1958)]; and K. Nagarjan, P. K. Talwalker, R. H. Shah and S. J. Shenoy, Indian J. Chem., Sect. B, 24B, 112 (1985).
The diphenyl ketyl radical has been reported to undergo substitution reactions with cyano-substituted puridinium ions to form .alpha.-pyridinium substituted carbinols. B. M. Vittimberga, F. Minisci and S. Morrocchi, J. Am. Chem. Soc., 97, 4397 (1975), reports such interactions in 1M sulfuric acid where the diphenyl ketyl radical was photochemically generated. In later work, P. McDevitt and B. M. Vittimberga, J. Heterocyclic Chem., 27, 1903 (1990), such interactions are described where the diphenyl ketyl radical was generated via thermal homolysis of benzopinacol. Interactions between thermally generated diphenyl ketyl radical and cyano-substituted pyridines in neutral media were also described in this later work.
Diaryl heterocyclic carbinols have been prepared by oxidation of corresponding methylpyridines with sodium hydroxide and O.sub.2 in DMOS. See, T. J. Kress and L. L. Moore, J. Heterocyclic Chem., 9, 1161 (1972).
As the above and other literature demostrates, the interest in discovering highly effective and economically attractive processes for producing .alpha.-pyridyl carbinols has been and remains substantial. However, routes heretofore studied present many disadvantages. For instance, the Emmert reaction gives mixtures of 2- and 4-pyridyl carbinols and it is thus not possible to achieve highly selective production of either. The Hammick reaction requires harsh conditions and gives low yields especially when working at the 4-position of the pyridine ring (e.g. with isonicotinic acid). The difficultly in handling organmetallics together with the use of halopyridines as starting materials makes the use of Grignard reagents unattractive from economic and other standpoints. Further, low yields and significant byproduct formation commonly encountered in the above-noted work with the diphenyl ketyl radical, and the expense of the corresponding methane starting materials in the above-noted work by Kress et al. make these routes relatively disadvantageous.
What is therefore needed is a process for producing .alpha.-pyridyl carbinols which employs relatively inexpensive starting materials and can be conducted under moderate conditions. Further, more preferred routes would provide high yields and minimal byproduct formation.